The transition from a fetus to a newborn is one of the most complex and challenging transitions that all humans have to undertake. While most infants make this transition with remarkable ease, a significant number of infants require some form of intervention to survive. But unfortunately, this intervention can inadvertently injure the infant causing life-long disability. We believe that with a better understanding of the processes involved, it is possible to minimize the risk of injury. Our primary aim is to increase our understanding of the physiology underpinning the transition from fetal to newborn life and to use this information to improve the strategies used to support infants in the delivery room, during this vital stage of their life. The recent 2010 neonatal resuscitation guidelines proposed by ILCOR has highlighted many areas of neonatal resuscitation where specific recommendations lack appropriate evidence to support current or proposed practices. We will endeavor to fill some of these critical gaps in knowledge so that improvements in neonatal health care are based on sound scientific evidence. Our unique proposal will use large and small animal models to investigate the most critical issues experienced by preterm infants during their transition to newborn life at birth. We will: (I) identify the most effective ways of initiating ventilation in te delivery room. Specifically we will focus on procedures that optimize lung recruitment, facilitate the increase in pulmonary hemodynamics and protect the brain from hemodynamic instability. (II) determine how a sustained inflation, given as the first breath after birth in severely asphyxi preterm lambs, rapidly restores cardiac function and whether this rapid response increases the risk of brain injury (III) determine the physiological basis underlying respiratory, cardiovascular and cerebral vascular improvements observed in response to delayed umbilical cord clamping, and determine the factors that alter these physiological responses. Our application incorporates a unique collaboration between clinicians, physiologists, physicists and engineers and utilizes the most advanced physiological, imaging and analytical capabilities currently available. Underpinning this application is our unique imaging capabilities, which allow for real-time assessment of lung aeration with a temporal and spatial resolution capable of imaging the smallest air sacs throughout a breath. Analysis of these images (developed by us) allows for accurate determination of regional lung volume, lung perfusion and lung tissue motion. Our proposal is focused on addressing the major issues facing clinicians and providing a strong physiological basis to improve the treatment of premature infants during the transition to newborn life at birth.